Gastrointestinal (GI) tract diseases were always central to medical concern due to their high prevalence. Of many diseases of this group gastric ulcers and duodenal ulcers have special social and medical significance, because their prevalence exceeds the prevalence of all other GI tract pathologies.
Medical treatment of peptic ulcer disease (PUD) aims to reduce the damaging effects of gastric acid (antisecretory drugs) on gastric tissues, raise the resistance of affected tissues, foremost of all gastric mucosa (gastroprotective drugs), and combat Helicobacter Pylori microorganisms (antimicrobial therapy).
The primary type of antiulcer treatment is periodic or sustained therapy using antisecretory drugs: proton pump inhibitors, histamine H2-receptor antagonists, antacid drugs, bismuth drugs (bismuth subsalicylate/subcitrate), sucralfate (a combination of aluminium hydroxide and sucrose octasulfate). Histamine H2-receptor antagonists, popular in the 1980s, have largely been superseded by more effective antisecretory drugs—proton pump inhibitors.
Proton pump inhibitors (PPIs) were first synthesized in 1976. The first PPIs were timoprazole and omeprazole. Timoprazole fell into obscurity, while omeprazole achieved widespread medical recognition. In 1988 Omeprazole was officially recommended for clinical use at the World Congress of Gastroenterology in Rome. One of the reasons for such recognition was the proof of its high efficacy in eliminating Helicobacter pylori (HP) bacteria, the discovery of which in 1983 has forced the medical community to review the nature of gastro duodenal diseases. Helicobacter infection received great attention because WHO experts recognized it as carcinogenic for humans after extensive research. That made the problem of HP eradication in gastric mucosa (and providing optimal conditions for ulcer healing) extremely important.
Despite omeprazole's widespread recognition and use as the first effective PPI, efforts to improve it continued. In 1992 specialists of Japanese firm Takeda have synthesized a new-generation PPI—lansoprazole. After a few years next-generation PPIs have appeared: pantoprazole, rabeprazole, esomeprazole.
Currently IPPs are the most widely used gastroduodenal ulcer treatment drugs in the world.
PPIs have been used for PUD treatment for over 15 years, however, their safety is not fully established. Dangerous adverse effects or life threatening PPI interactions with other drugs sometimes may be discovered only after extensive use—hundreds of thousands uses may be required. However, even now adverse effects of PPI (mainly omeprazole) on liver are documented in children [1]. Clinical use has also shown other adverse effects: diarrhea, nausea, abdominal colic, drowsiness, and headaches.
Long-term use of omeprazole and other PPIs (as well as some other antisecretory drugs) may lead to a potent and prolonged inhibition of gastric secretion and sometimes atrophy of gastric secretory cells, causing severe complications (development of tumors like gastrinoma, adenocarcinoma, Helicobacter Pylori infestation, intestinal infections, intestinal malabsorption of fats, minerals and vitamins). All of these complications are described in the following literature: [2]. In addition, it should be taken into account that PPI metabolism involves cytochrome P450 oxidase system, so long-term PPI use may cause tolerance to such drugs after this enzyme system's activity is exhausted [3]. This may be connected to the known withdrawal syndrome—relapse of the disease after some time (from 2 to 22 weeks, average 14 weeks) of omeprazole cancellation [4].
Other adverse and undesirable effects are known in drugs of this class, which are usually shown in indications for use (headache, diarrhea, allergy, gynecomastia, etc).
PPIs are thus quite effective drugs, widely used in PUD treatment, however they also have adverse effects and negative consequences (the most dangerous of them, possibly lethal, is infestation by Helicobacter pylori and tumor development). Also, they are sometimes ineffective in treatment. This makes the search for new antiulcer drugs important and relevant.
The most promising venue of new antiulcer drug development is synthesizing a drug with gastroprotective properties, as this does not cause “hard” inhibition of gastric secretion. The latter causes the main adverse effects—Helicobacter pylori infestation and tumor processes Inhibition may be undesirable, when secretion levels are normal or low, which is frequently encountered during PUD. In such case all that is needed is to “protect” gastric mucosa from irritation, so that the damaged mucosa was not further damaged by acid, but instead protected from it.
Such drugs are usually based on prostaglandins. Prostaglandins stimulate mucus secretion and activate protein kinase, which, by acting on cell membrane, can protect gastric mucosa from aggressive effects of acid and pepsin. On the other hand, prostaglandins can inhibit gastric acid secretion. This combined action makes prostaglandins very promising antiulcer drugs, however, there is little experience of their use, currently they are only at clinical trials stage [5].
Another promising venue is the development of gastroprotective drugs—NO donors. Nitric oxide acts as a multifunctional gastroprotective mediator, affecting some aspects of GI tract action, including bile and bicarbonate secretion and blood flow in GI tract walls [6]. NO also possesses antimicrobial properties, in particular towards Helicobacter pylori bacteria [7]. NO donors do not have direct antisecretory effect, but bicarbonate, secreted under their influence in stomach, interacts with gastric acid, neutralizing it.
Other drugs are used to inhibit gastric acid secretion: H2-receptor antagonists (famotidine, ranitidine, cimetidine) and proton pump inhibitors. H2-receptor antagonists have significant drawbacks compared to PPIs: a) they block only the signal created during histamine binding, b) their action is reversible and they eliminate quickly from the bloodstream, forcing a patient to take several pills a day. Their use also leads to intense histamine receptor synthesis, causing “rebounds” of HCL secretion after their cancellation.
The first proton pump inhibitor in the market was omeprazole (AstraZeneca), a substituted benzimidazole which appeared in the 80s. PPIs currently present in the market are also substituted benzimidazoles. They are: nexium (S-enantiomer of omeprazole or esomeprazole, AstraZeneca), multiple omeprazole generics, pariet (rabeprazole, Janssen-Cilag) and controloc (pantoprazole, Byk Gulden, not sold in Russia). All these compounds are prodrugs. They are weak bases, and being exposed to the acidic environment of parietal vesicles they bind H+ and undergo molecular transformation into the drug—an active sulfenamide interacting with SH-groups of H-ATPase in secretory vesicle. Sulfenamides form covalent bond with SH groups, so their action is irreversible. Their action stops only after the elimination of H-ATPase molecule, modified by an inhibitor, and half-life of H,K-ATPase in humans is about 40 hours. This makes second-generation PPIs like pariet and nexium highly effective in treating acid-dependent diseases. PUD treatment using these inhibitors combined with antibiotics, eliminating Helicobacter pylori infection, is effective in 90% of cases [20].
In addition to irreversible proton pump inhibitors, reversible inhibitors also exist, however there are currently no drugs based on them. This is probably due to very high efficacy and safety of irreversible PPIs.
Among reversible PPIs the most well-known one is imidazopyridine SCH-28080 which inhibits H,K-ATPase by K+-competitive mechanism with Ki (inhibition constant) of 0.2-0.24 μmol [21].SCH-28080 analogs interact with a fragment of H,K-ATPase's 44 amino-acid residues long a-subunit, starting with Leu-854 and ending with Arg-897. This fragment is homologous to the one of H,K-ATPase, which SCH-28080 also inhibit, but with less affinity. Apparently it represents the K-binding center of these related enzymes. Besides SCH-28080 other more specific inhibitors are known—SK&F that inhibits only H,K-ATPase with 0.5 μmol and competes with SCH-28080 and K+ and SK&F96356 that inhibits H,K-ATPase with Ki=0.07 μmol, also competing with SCH-28080 and K+.
The drug SCH 28080 with a formula:

can be considered the closest analog [19]. The compound is effective, however competitive action to K+ ions is possible, which can lead to negative adverse effects.